Global prognostic impact of driver genetic alterations in patients with lung adenocarcinoma: a real-life study.

Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring driver genetic alterations. A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of low-frequency EGFR-T790M mutated alleles at baseline). The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18-21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs) agents, had a significantly longer survival in comparison to those without (p < 0.0001); conversely, KRAS mutations were associated with a significantly lower survival (p = 0.0058). Among LAC patients with additional tissue section available for next-generation sequencing (NGS)-based analysis, 26/193 (13.5%) patients found positive for even low-rate EGFR-T790M mutated alleles at baseline were associated with a highly significant lower survival in comparison to those without (8.7 vs. 47.4 months, p < 0.0001). In addition to its predictive value for addressing targeted therapy approaches, the assessment of as more inclusive mutation analysis at baseline may provide clues about factors significantly impacting on global survival in advanced LAC patients.

Paliogiannis P ，Colombino M ，Sini MC ，Manca A ，Casula M ，Palomba G ，Pisano M ，Doneddu V ，Zinellu A ，Santeufemia D ，Sardinian Lung Cancer (SLC) Study Group ，Sotgiu G ，Cossu A ，Palmieri G ... -  《BMC Pulmonary Medicine》

EGFR, KRAS, BRAF, ALK, and cMET genetic alterations in 1440 Sardinian patients with lung adenocarcinoma.

Colombino M ，Paliogiannis P ，Cossu A ，Santeufemia DA ，Sardinian Lung Cancer (SLC) Study Group ，Sini MC ，Casula M ，Palomba G ，Manca A ，Pisano M ，Doneddu V ，Palmieri G ... -  《BMC Pulmonary Medicine》

[Correlation between common driver gene variations and clinicopathological typing in lung adenocarcinoma].

Ma XL ，Jia RN ，Han K ，Zhang YX ... -  《-》

Response rate of patients with baseline brain metastases from recently diagnosed non-small cell lung cancer receiving radiotherapy according to EGFR, ALK and KRAS mutation status.

Previous studies have identified that patients with EGFR mutations tend to have better responses to targeted therapy, as well as chemotherapy; however, the effect of genetic alterations in terms of radiotherapy (RT)-related outcomes has not been fully assessed. We studied the impact of common non-small cell lung cancer (NSCLC) genetic alterations (EGFR, ALK and KRAS) in relation to objective response rate (ORR) to RT in patients with brain metastases. From 2009-2015, 153 patients with an available genotyping status were treated with whole-brain irradiation (WBI) before receiving systemic therapy. Primary outcome was ORR; secondary outcomes included intracranial progression-free survival (IPFS) and overall survival (OS). Overall, ORR was 47.1%. ORR to RT varied significantly according to molecular status: EGFR (64.5%) ALK (54.5%) KRAS (20%) and WT (35.4%) (P = 0.001). EGFR mutation was the only independently associated factor for response to WBI (RR 3.52 [95% CI 1.6-7.7]; P = 0.002). Median IPFS was 10.8 months [95% CI 8.2-13.5] overall; however, IPFS also varied significantly according to molecular status: EGFR (18.2 months), ALK (18.4 months), KRAS (6.0 months) and WT (8.7 months) (P < 0.0001). OS for EGFR, ALK, KRAS and WT patients was 36.6, 32.2, 15.5 and 22.4 months, respectively (P = 0.014). Intracranial-ORR (HR 0.4 [95% CI 0.2-0.6], P < 0.001) and mutation status (HR 0.7 [95% CI 0.6-0.9], P < 0.042) were independently associated with a higher OS. RT response varies as per tumor molecular status. The presence of EGFR mutations favors the organ-specific response to RT, and is associated with longer OS in patients with NSCLC and BM. This study addressed for the first time the difference in radiotherapy-related outcomes in patients with different genotypes of non-small cell lung cancer (NSCLC) before they received systemic therapy. Results show that response to radiotherapy varies as per tumor molecular status, particularly EGFR-mutated tumors, have a favorable response to radiotherapy, contrary to KRAS-mutated tumors.

Arrieta O ，Ramírez-Tirado LA ，Caballé-Perez E ，Mejia-Perez A ，Zatarain-Barrón ZL ，Cardona AF ，Lozano-Ruíz F ，Segura-González M ，Cruz-Rico G ，Maldonado F ，Rosell R ... -  《-》

Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium.

The advent of effective targeted therapy for BRAF(V600E) -mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced-stage BRAF-mutant lung adenocarcinomas. Data were reviewed for patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), human epidermal growth factor receptor 2 (HER2), AKT1, BRAF, dual-specificity mitogen-activated protein kinase kinase 1 (MEK1), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA); for anaplastic lymphoma kinase (ALK) translocations; and for MET amplification. Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%; 95% confidence interval [CI], 1.4%-3.4%): 17 (81%; 95% CI, 60%-92%) were BRAF(V600E) mutations, and 4 were non-BRAF(V600E) mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur than most other genotypic abnormalities in current or former smokers (BRAF vs sensitizing EGFR, 82% vs 36%, mid-P < .001; BRAF vs ALK, 39%, mid-P = .003; BRAF vs other mutations, 49%, mid-P = .02; BRAF vs patients with more than 1 oncogenic driver [doubleton], 46%, mid-P = .04.) The double-mutation rate was 16% among patients with BRAF mutations but 5% among patients with other genomic abnormalities (mid-P = .045). Differences were not found in survival between patients with BRAF mutations and those with other genomic abnormalities (P > .20). BRAF mutations occurred in 2.2% of advanced-stage lung adenocarcinomas, were most commonly V600E, and were associated with distinct clinicopathologic features in comparison with other genomic subtypes and with a high mutation rate in more than 1 gene. These findings underscore the importance of comprehensive genomic profiling in assessing patients with advanced lung adenocarcinomas.

Villaruz LC ，Socinski MA ，Abberbock S ，Berry LD ，Johnson BE ，Kwiatkowski DJ ，Iafrate AJ ，Varella-Garcia M ，Franklin WA ，Camidge DR ，Sequist LV ，Haura EB ，Ladanyi M ，Kurland BF ，Kugler K ，Minna JD ，Bunn PA ，Kris MG ... -  《-》